; The overall goal of this work is to elucidate and mitigate mechanisms of maladaptive metabolic remodeling that may contribute to cardiac dysfunction and the progression to decompensated hypertrophy in the pressure overloaded heart. The proposal originates from two novel findings in our laboratory: 1) that stored triglyceride (TG) in the heart is quite dynamic, but TG turnover is slow in the failing heart as is TG content, the latter finding since being confirmed in heart failure patients without diabetes. The loss of TG turnover reduces the contribution of long chain fatty acids (LCFA) from TG to mitochondrial fatty acid oxidation (FAO) and importantly, impairs TG lipolytic activation of PPAR?. We have reported that while palmitate sustains this reduced TG metabolism and PPAR? activation in hypertrophied hearts, oleate normalizes each of these very same parameters; 2) our lab first reported increased protein content of the liver isoform of the rate limiting enzyme in FAO, carnitine palmitoyltransferase I (CPT1) in hypertrophied hearts. We also found acute expression of the liver CPT1 (CPT1a) in healthy hearts induced two surprising results; a paradoxical reduction in FAO and elevated myocardial atrial natriuretic peptide mRNA, both classically observed responses to pathogenic stress. Preliminary data show CPT1a expression is suppressed by Mir-370 and that Mir370 content is low in hypertrophied hearts. Thus, we hypothesize that: 1) Supplying an oleate rich diet provides benefits to rat hearts following transverse aortic constriction (TAC) by a) maintaining TG turnover and PPAR? target gene expression, b) influencing the formation of ceramide species, and c) thereby attenuating dysfunction and decompensation. 2) Increased CPT1a in hypertrophied hearts is a key step in the early metabolic remodeling that influences cardiac decompensation and is linked to hypertrophic signaling. 3) Increased CPT1a in hypertrophied hearts is linked to reduce FAO via changes in CPT1 acetylation and malonylation, and these changes respond to CPT1a regulation via restored Mir-370 content. Aim 1 a) determines effects of palmitate- (tripalmitin) versus oleate-rich (triolein) diets on decompensation after TAC in rat hearts, and b) determines if triolein and tripalmitin diets post-TAC affect TG turnover, PPAR? target gene expression, LCFA oxidation and lipotoxic acyl-intermediates. Aim 2 determines the role of the isoform shift to CPT1a (liver) expression in the reduced LCFA oxidation and progression toward decompensation and early HF. Cardiac specific, CPT1a null mice, that are unable increase CPT1a in response to TAC, will be examined for functional and hypertrophic responses to TAC. The potential for altered FAO through exclusive changes in CPT1b (muscle isoform) content and CPT1 acetylation/malonylation, will be elucidated in the restricted absence of a CPT1a response. Aim 3 elucidates potentially maladaptive upregulation of CPT1a, due to reduced Mir-370 during TAC, and the role of CPT1a expression in acetylation and malonylation of both CPT1 isoforms. Low Mir-370 following TAC in rat hearts will be countered by acutely overexpressing Mir-370 to suppress CPT1a and downstream effects.